This invention relates generally to new peptides and particularly to new synthetic peptides which induce selective B-cell differentiation.
Two main classes of lymphocytes occur in the immune system of vertebrate animals: (1) T-lymphocytes or T-cells, which differentiate in the thymus, and (2) B-lymphocytes or B-cells, which differentiate in the Bursa of Fabricius of birds and presumably in some homologous organ in vertebrates, which have no bursa. The immediate precursors of T-cells and B-cells are found in the bone marrow and are induced by specific hormones or "inducers" to differentiate into the mature cells. In the case of T-cells, the inducer is the polypeptide thymopoietin, which has been extensively studied. See, for example, U.S. Pat. Nos. 4,002,740, 4,077,949, and 4,190,646, of which one of the inventors herein is either the inventor or a co-inventor.
To provide a general understanding of the importance of the differentiating biological characteristics of the peptides of this invention, it should be noted that the function of the thymus in relation to immunity may be broadly stated as the production of thymus-derived lymphocytes (called T-cells). T-cells form a large proportion of the pool of recirculating small lymphocytes. They have immunological specificity and are directly involved in cell-mediated immune responses (such as homograft responses) as effector cells. T-cells, however, do not secrete antibodies, this function being performed by a separate class of lymphocytes termed B-cells. B-cells are derived from precursor B-cells in the bone marrow independent of thymic influence. In birds, they are differentiated in an organ analogous to the thymus which is called the Bursa of Fabricius. In mammals, no equivalent organ has been discovered, and it is thought that B-cells may differentiate within the bone marrow itself. The physiological substance dictating this differentiation remained completely unknown until the present invention.
In early studies by one of the present inventors and others, the existence of a specific B-cell differentiating inducer was demonstrated in extracts of the Bursa of Fabricius from chickens. The active material in this extract was not characterized, although the authors of one of the early articles stated that they "infer that it is a small polypeptide" and named it "bursopoietin." This early work is reported in the following articles, which are incorporated herein by reference: Brand, et. al., Science, Volume 193, pgs. 319-321 (July 23, 1976); Brand, et. al., Nature, Vol. 269, pgs. 597-598 (Oct. 13, 1977); Goldstein, et. al., Cold Spring Harbor Symposia on Quantitative Biology, Vol. XLI, pgs. 5-8 (1977); and Goldstein, in "Molecular Control of Proliferation and Differentiation", pgs. 197-202, Academic Press (1977). More recently, the present inventors have described the structure of bursopoietin in Science, Volume 231, pgs. 997-999, (February 1986).
The discovery of a specific B-cell differentiating factor would be of considerable value in understanding the immune function and in diagnosing and treating various immune disorders in humans and animals. For example, a rare but potentially fatal disease called hypogammaglobulinemia manifests itself as an inability or severe deficiency of an individual to produce antibodies. Such an individual is susceptible to unchecked infection and has a relatively short life expectancy. While it is believed that this disease may have several causes, at least one cause is the absence of functional B-cells. If the absence of functional B-cells is due to an underproduction of the B-cell differentiating hormone, administration of this hormone would restore the patient to normal.
The present invention provides synthetic 3-amino acid peptides having the specific B-cell differentiating function of bursopoietin.